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Can RNA Turn Genes On?

Researchers at the University of Texas Southwestern Medical Center have found that RNA may be a potential tool in activating dormant genes.

This week, more than 700 scientists have flocked to the ski resort of Keystone, Colorado, for five days. But it’s not the snow that’s brought them together. Rather, it’s something they find much more exciting: RNA–a tiny cousin of DNA that may be the key to developing genetic therapies for a huge range of diseases, including cancer, neurological and respiratory diseases, and HIV.

Professor of pharmacology David Corey, graduate student Rosalyn Ram, and assistant professor of pharmacology Bethany Janowski have activated certain genes in cultured cells using strands of RNA. The RNA perturbs the mixture of proteins that surround chromosomal DNA–proteins that control whether genes are turned on or off. The new technique could lead to therapeutics for conditions in which nudging a gene awake would help alleviate disease.

Nearly eight years ago, researchers Craig Mello, of the University of Massachusetts Medical School, and Andrew Fire, of Stanford University’s School of Medicine, discovered that RNA plays a crucial role in regulating gene expression: the ability to turn genes off. They won a Nobel Prize for their work in 2006 identifying the mechanism for a process called RNA interference, or RNAi. They found that RNA blocks a gene from delivering its message to proteins, essentially shutting down that gene. Since then, scientists around the world have run with the idea, finding ways for RNAi to turn off a variety of genes–in particular, those that cause disease. It’s RNA’s role in switching off genes that dominates the talks at this week’s conference, titled “RNAi for Target Validation and as a Therapeutic.”

However, not much is known about RNA’s role, if any, in turning genes on. It’s a phenomenon that researchers Bethany Janowski and David Corey stumbled upon a couple years ago, almost by accident. Their study, published in NatureChemical Biology, provides evidence of RNA’s genetic “on” switch, and they’ve presented their findings at this week’s conference.

In 2005, Janowski and Corey, both at the University of Texas Southwestern Medical Center, were studying the effects of RNA in turning off certain genes related to breast cancer. Specifically, they found that injecting RNA strands into cultures of human breast-cancer cells with high levels of progesterone receptors inhibited the gene that controlled for that receptor. (It’s been found that varying levels of the hormone progesterone affects the growth of cancer cells.) As a result, the team observed a reduced level of progesterone production.

After a closer look, Janowski and Corey also found that a small number of RNA strands had the opposite effect, causing a slight increase in gene activation–an effect they did not expect. Investigating further, they isolated the activating RNA strands, then injected them into a culture of cancer cells with low levels of progesterone receptors. The result: RNA actually turned up gene expression for these receptors, stimulating the gene to produce more progesterone.

“It really goes against the dogma out there,” says Janowski, assistant professor of pharmacology and lead author of the study. “The idea that RNA can be a major regulator is something that people have to get used to. But on a biological level, it makes perfect sense. If RNA can silence, it should be able to turn on.”

The ability to turn genes both on and off may have major implications for the treatment of diseases. For example, the development of cancer may be partially due to mutations in genes that control cell growth. The body contains genes that are natural tumor suppressors. Mutations that silence these genes may result in uncontrolled cancer growth. Janowski and Corey believe that finding a way to turn these genes back on may stem the growth of tumor cells.

However, they say it’s not clear exactly how RNA’s genetic “on” switch works. In their experiments, the researchers injected RNA directly into cancer cells, where it interacted with specific genes to turn them on. Janowski says this may be a more direct method compared with conventional RNAi techniques, in which scientists inject RNA strands outside a cell to block messenger RNA–an intermediary molecule that delivers genetic information out of a cell to surrounding proteins that act out a gene’s instructions.

“It’s easier to turn something off by acting like a roadblock so the transcriptional machinery can’t get past it,” says Janowski. “But to activate it is harder to do.”

Gordon Carmichael, professor of genetics and developmental biology at the University of Connecticut Health Center, studies RNA’s role in regulating disease. While Carmichael did not attend the conference, he is familiar with the team’s work and says the research is interesting, although puzzling. “The question arises as to whether the observed effects are general and, if so, how general?” he says. “There appear to be few genes that can be regulated this way.”

In future studies, Janowski and Corey plan to explore the exact mechanism for RNA’s genetic activating potential. They will also explore RNA’s effect in turning on a variety of genes, including tumor suppressor genes, and they hope eventually to experiment on animal models. However, Janowski acknowledges that the team’s work and its conclusions are preliminary.

Phillip Sharp, MIT professor and Nobel Prize-winning cancer researcher, advises a wait-and-see approach. Speaking from the RNAi conference in Colorado, Sharp says it may be a while before RNA’s genetic “on” switch is as scientifically confirmed as its “off” switch. “There will have to be a lot of additional work before one can judge the importance of this finding,” he says.

The University of Texas team, meanwhile, is optimistic. “Anything new will be a test of time,” says Janowski. “People are pretty open to new ideas, but because this has been so entrenched, it will take people a while to get a handle on this.”

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